# Investigating KCNQ1 Mistrafficking in Long QT Syndrome

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $29,591

## Abstract

Project Summary
 Long QT syndrome (LQTS) is a cardiac disorder characterized by the prolongation of the latter
portion of the electrocardiogram trace (the QT interval) that increases risk of cardiac arrythmia, cardiac
arrest, and sudden unexpected death. Approximately 1 in 2500 individuals suffer from the congenital
form of LQTS, with 30-50% of cases being caused by mutations in the voltage gated potassium
channel protein KCNQ1 (type 1 LQTS, or LQT1). Over 250 LQT1-associated mutations in KCNQ1 have
been identified, but the impact of these mutations on the channel’s structure and function, and whether
there are common mechanisms through which these mutations lead to KCNQ1 dysfunction in LQT1, is
still unknown. The primary goal of this proposed project is to explore mistrafficking as a potential
mechanism of KCNQ1 loss of function in long QT syndrome.
 Previous studies of LQT1-associated mutations in the KCNQ1 voltage sensing domain (VSD)
found that the majority decreased KCNQ1 trafficking to the plasma membrane and destabilized the
VSD. Additional studies have shown that mutations in KCNQ1 can lead to retention in the endoplasmic
reticulum (ER) and increased proteasomal degradation. This has led to the hypothesis that
mistrafficking is a common mechanism of protein dysfunction in LQT1. Mistrafficking has been
identified as a disease mechanism in several other membrane-protein associated diseases, such as
cystic fibrosis and retinitis pigmentosa, and in the case of cystic fibrosis, drugs have been developed to
rescue mistrafficking and alleviate disease symptoms. This leads to the additional hypothesis that drugs
that bind nascent KCNQ1 channels and increase their stability can increase the trafficking of KCNQ1.
 In line with these hypotheses, I propose two aims: 1) to classify mutations across KCNQ1 based
on their impact on KCNQ1 trafficking, and 2) to develop a high throughput screening method to identify
small molecules that increase cell surface trafficking. In Aim 1, I will classify the trafficking of all
possible KCNQ1 variants with a fluorescence-activated cell sorting (FACS)-based deep mutational
scanning method. This will allow me to determine whether the majority of LQT1-associated mutations
cause mistrafficking and also provide information on variants of unknown significance (VUS) and other
KCNQ1 variants. In Aim 2, I will utilize immunofluorescence and high content imaging to screen for
small molecules that increase WT or mutant KCNQ1 trafficking. This will test the hypothesis that
KCNQ1 mistrafficking is rescuable with small molecules. Together, the results of these aims will provide
further insight into the molecular mechanisms behind KCNQ1 dysfunction in LQT1 and explore a
possible route for developing novel treatments for LQT1.

## Key facts

- **NIH application ID:** 10938003
- **Project number:** 5F31HL168964-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Katherine R Moster
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $29,591
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938003

## Citation

> US National Institutes of Health, RePORTER application 10938003, Investigating KCNQ1 Mistrafficking in Long QT Syndrome (5F31HL168964-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10938003. Licensed CC0.

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